CHARACTERIZATION OF HALOPERIDOL AND TRIFLUPERIDOL AS SUBTYPE-SELECTIVE N-METHYL-D-ASPARTATE (NMDA) RECEPTOR ANTAGONISTS USING [H-3] TCP AND[H-3] IFENPRODIL BINDING IN RAT-BRAIN MEMBRANES

[H-3]TCP and [H-3]ifenprodil binding to N-methyl-D-aspartate (NMDA) re ceptors in rat forebrain membranes was used to compare the inhibition of haloperidol and trifluperidol with that of ifenprodil and eliprodil . In the [H-3]TCP binding assay, inhibition curves of ifenprodil, elip rodil, haloperidol and trifluperidol revealed two affinity states in t he presence of glutamate, glycine and spermidine. The potency of these agents to inhibit the high-affinity fraction of the binding agreed wi th the results of other studies investigating their potency to block g lutamate-induced current at recombinant NR1a/NR2B NMDA receptors expre ssed in Xenopus oocytes. These agents also inhibited [H-3]ifenprodil b inding in a biphasic manner, whether in the absence or the presence of either the sigma site ligand GBR-12909 or spermidine. Spermidine redu ced the fraction of high-affinity sites labeled with [H-3]ifenprodil. The only alteration in the affinity was a decrease in the IC50 value o f haloperidol to inhibit the high-affinity fraction of [H-3]ifenprodil binding. GBR-12909 also reduced the fraction of [H-3]ifenprodil sites inhibited by these compounds with high affinity, with no change in th e affinity for either fraction. These data suggest that spermidine is neither a competitive antagonist at the fraction of the binding inhibi ted by these agents with high affinity, nor is this fraction of the bi nding to sigma sites. Haloperidol and trifluperidol represent a new cl ass of agent that interacts at a site that is labeled by [H-3]ifenprod il as well as [H-3]TCP in rat brain membranes and that closely reflect s ifenprodil's voltage-independent site on the recombinant NR1a/NR2B s ubtype of the NMDA receptor.